VU University Amsterdam research suggest older the population becomes, the more significant a problem heart failure will be for society because of stiffening of the muscle wall of the left ventricle

The older the population becomes, the more significant a problem heart failure will be for society. In Western European countries, heart failure is now the leading cause of hospital admissions. Until now, it has always been thought to result from a reduction in the capacity of the heart to contract. However, this explanation has recently become the subject of some doubt, because in more than 50% of cases of heart failure, no such reduction occurs.

The heart failure detected in these patients can be ascribed to a stiffening of the muscle wall of the left ventricle. This means that greater pressure is needed from the lungs during the diastole or relaxation phase of the heart in order to properly fill the left ventricle. This type of heart failure is often referred to as diastolic heart failure, and usually occurs in older obese women with high blood pressure and diabetes. Greater lung pressure causes shortage of breath and serious pulmonary oedema – a build up of fluid in the lung cavities. Stiffening of the heart can be caused by:

a build- up of connective tissue between the heart muscle cells;

a build-up of sugar-binding proteins;

loss of elasticity of the heart muscle cells themselves.

A) Histology of heart muscle biopsy with varying amounts of connective tissue in the biopsy between the heart muscle cells;
B) Build-up of sugar-binding proteins in the small vessels in a heart muscle biopsy;
C) Build-up of inflammation protein in the vessel of a heart muscle biopsy;
D) Heart muscle cell isolated from a biopsy with an enlargement of the sarcomeric structure (arrows);
E) Heart muscle biopsy viewed through an electron microscope.

Build-up of connective tissue

The Institute for Cardiovascular Research of VU University Amsterdam (ICaR-VU) has conducted research into this by looking for the causes of heart stiffening in pieces of heart muscle tissue from patients who have suffered from diastolic heart failure. These pieces of tissue were removed from the heart muscle wall during heart catheterization with a long thin instrument known as a bioptome. Much to the surprise of the researchers, patients with diastolic heart failure had less build-up of connective tissue and of sugar-binding proteins than did patients with systolic heart failure, or heart failure resulting from a reduction in the heart’s capacity to contract.

However, the elasticity of the heart muscle cells was badly damaged in patients with diastolic heart failure; this is controlled by a very large protein that links both ends of the heart muscle cells and works like a spring. The protein is the largest known and is referred to as titin on account of its enormous dimensions. The heart muscle cell can modify the spring-like qualities of titin, and does so in three different ways:

1. by making a slight change to the composition of the protein so that it loses some of its elasticity;
2. by attaching a phosphate to the protein;
3. by releasing sulphur bridges in the protein, making it more flexible.

Researchers at ICaR-VU discovered that these three mechanisms had been disrupted in the case of patients with diastolic heart failure:

too much titin was stiff in composition;

there was not enough titin with phosphate attached;

too many sulphur bridges remained attached.

These new insights have opened the way towards more efficient therapy for diastolic heart failure. After all, patients with diastolic heart failure do not respond well enough to current heart failure treatment. Drugs that attach phosphate to titin and release sulphur bridges are being tested.

Because of this groundbreaking work into the stiffening of the heart, the ICaR-VU is acknowledged as a leader in the field of diastolic heart failure. New European guidelines for diagnosing diastolic heart failure were laid down under the direction of the ICaR-VU, and with the support of the Nederlandse Hartstichting (Dutch heart foundation), it coordinates a major European research consortium into this notable type of heart failure.
Credit : VU University Amsterdam